A few disubstituted or trisubstituted indole and bis-indole derivatives are already known in the art as having therapeutic activity, as shown by the following brief review. 3,5-disubstituted indoles such as serotonine and melatonine are well known. 2,3-disubstituted indoles wherein the 2- and 3-substituents together form a ring next to the pyrrole ring are known e.g. from U.S. Pat. No. 4,430,269, U.S. Pat. No. 5,811,551 and U.S. Pat. No. 6,147,076. U.S. Pat. No. 5,808,064 further discloses 2,3-disubsbtuted indoles wherein the 2-substituent is a trialkylsilyl or triphenylsilyl group. U.S. Pat. No. 5,877,329 discloses 2,3,5-trisubstituted indoles being useful intermediates in preparing biologically active compounds such as certain lipoxygenase inhibitors. U.S. Pat. No. 5,932,743 discloses 2,3-disubstituted indole-6-carboxylic acids having estrogen agonist activity. U.S. Pat. No. 5,573,999 discloses that 2,4-disubstituted indoles can be prepared from 2-haloanilines and enamines in the presence of a Pd compound (J. Heterocycl. Chem. (1987) 24:1555). U.S. Pat. No. 3,954,799 discloses that synthesis of 1,3-disubstituted indoles generally requires the vigorous conditions used by Norland et al., J. Am. Chem. Soc. (1960) 82:5143 for the condensation of 2-carboxybenzaldehyde and indoles. U.S. Pat. No. 6,245,761 discloses alkylation of 1,2-disubstituted indoles by way of a Mannich reaction.
With respect to bis-indoles, however, a few disubstituted bis-indoles are already known in the art. A first class of 2,2′-dicarboxylic acid (ester)-5,5′-diindolyl derivatives wherein the indole groups are linked through a single bond, oxygen, sulfur, methylene or ethylene, all being made with yields ranging from 46 to 67% by the cyclization of dihydrazones, are known from the publications of Samsonyia et al. in Chem. Heterocycl. Compds (1981) 1:57–61 and Chem. Heterocycl. Compds (1982) 3:348–351. Additionally, Chemical Abstracts (1961) 55:5457 discloses making 2,2′-dicarboxylic acid (ester)-3,3′-diindolyl sulfide with a 40% yield by reacting SOCl2 with indole-2-carboxylate. Chem. Heterocycl. Compds (1978) 2:217–224 discloses making 2,2′-dicarbethoxy-3,5′-diindolyl with a yield of 35% by the cyclization of a hydrazone.
EP-A-887.348 additionally discloses substituted [bis-indol-3-yl)methyl] benzenes wherein the phenyl group of the indole linking bridge is substituted with hydroxy or carboxy, and wherein the phenyl rings of the indole groups are symmetrically substituted in the 5-position or 6-position with hydroxy, bromo, amino, methylamino, diethylamino, isopropyl or ethylthio, these compounds being useful as antitumor and antimetastatic agents. The same document also discloses another type of disubstituted bis-indole, namely 2,3-dihydroxy-1-[bis(2-hydroxyindol-3-yl)methyl] benzene. These compounds can be prepared by condensing benzaldehyde with at least two equivalents of a substituted indole.
International patent application published as WO 98/50357 discloses a group of 5,5′-disubstituted- or 2,2′-disubstituted- or N,N′-disubstituted-3,3′-diindolylmethanes being useful as antiestrogens. In particular there are disclosed 2,2′-di(C1–C5)alkyl-3,3′-diindolylmethanes, 1,1′-di(C1–C5)alkyl-3,3′-diindolyl-methanes, 5,5′-dihalo-3,3′-diindolylmethanes, 5,5′-di(C1–C5)alkyl-3,3′-diindolyl-methanes and 5,5′-di(C1–C5)alkoxy-3,3′-diindolylmethanes. They can be obtained by condensing formaldehyde with commercially available substituted indoles, although this has the disadvantage of forming by-products which complicate purification of the desired product. Therefore a preferred synthesis in three steps consists of first forming a substituted indole-3-aldehyde, then reducing it into the corresponding substituted indole-3-methanol which is then condensed for example by treatment with a phosphate buffer having a pH around 5.5.
International patent application published as WO 00/09169 discloses a class of labeled non-porphyrin compounds being e.g. applicable as diagnostic agents in Magnetic Resonance Imaging applications or nuclear medicine, these compounds comprising (i) an agent suitable for targeting a specific organ and/or tissue and comprising one or more organic ring compounds, (ii) an agent suitable for labeling the targeted organ and/or tissue, and optionally (iii) a spacing agent arranged between the targeting agent and the labeling agent. Primarily described in the latter document are pamoic acid derivatives, i.e. compounds wherein the labeling agent and optionally the spacing agent are in β position with respect to the linking agent. Some of these compounds, such as the gadolinium complex of a bis-diethylenetriaminepentaacetic acid pamoic acid derivative obtained from 3-hydroxy-2-naphtalene methyl carboxylate through its reaction with hydrazine, exhibit a unique targetability to necrotic tissues. Such pamoic acid derivatives however exhibit some shortcomings. First, solutions of these compounds with concentrations useful for medical applications are not colorless and, during long term storage, may encounter significant discoloration of pharmaceutical preparations containing them. For instance, a 0.25 mmolar solution of the said gadolinium complex of the bis-diethylenetriaminepentaacetic acid pamoic acid derivative obtained from 3-hydroxy-2-naphtalene methyl carboxylate has a yellow-orange color and has an absorbance of 0.75 at 400 nm. Secondly, despite their relatively high LD50 values, significant side effects (e.g. myocarditis) were observed in animals having received an intravenous bolus injection of 1 mmole of the said gadolinium complex per kg body weight.
As a summary, the state of the art provides six different classes of disubstituted bis-indoles, being respectively the symmetrical 1,3-disubstitution, 2,3-disubstitution, 2,5-disubstitution, 3,5-disubstitution and 3,6-disubstitution and the disymmetrical 2,2′,3,5′-substitution of a bis-indolyl basic structure. In addition to the said six classes actually disclosed in the art, 1,2- and 2,4-disubstituted indoles are also respectively available, which could in principle be condensed, using coupling procedures standard in the art, in order to achieve the corresponding disubstituted bis-indoles. However, with very few exceptions, the bis-indoles bearing carboxylic acid ester substituents described so far are either symmetrical 2,5disubstituted bis-indoles or the disymmetrical 2,2′,3,5′-substituted bis-indoles.
In view of the prevalence of cerebral and myocardial infarction and of other necrosis related phenomena, It would be of great importance to provide contrast agents, in particular multipurpose contrast agents and tissue-specific contrast agents which would be in vivo effective for the identification, localization and therapeutic follow-up of pathological tissue disorders, in particular those resulting from ischemic diseases and space-occupying lesions, including necrosis, but which would not suffer from the above-mentioned drawbacks (significant discoloration upon long-term storage, myocardial toxicity) of the pamoic acid derivatives known in the art. There is also a need in the art for pharmaceutical compositions including tissue-specific and/or multipurpose contrast agents which are suitable for use in magnetic resonance imaging and nuclear scintigraphy imaging technologies while requiring only low doses of the active agent. It is therefore the goal of the present invention to provide useful compounds meeting these various criteria, as well as a suitable and cost-effective manufacturing route for their synthesis.